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Rather than me doing a mildly educated guess, here is some evidence from greater experts than I'll ever be:

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One of the earliest theoretical studies of the distribution of fitness effects was done by Motoo Kimura, an influential theoretical population geneticist. His neutral theory of molecular evolution proposes that most novel mutations will be highly deleterious, with a small fraction being neutral. Hiroshi Akashi more recently proposed a bimodal model for DFE, with modes centered around highly deleterious and neutral mutations. Both theories agree that the vast majority of novel mutations are neutral or deleterious and that advantageous mutations are rare, which has been supported by experimental results. One example is a study done on the distribution of fitness effects of random mutations in vesicular stomatitis virus. Out of all mutations, 39.6% were lethal, 31.2% were non-lethal deleterious, and 27.1% were neutral.

I corrected your link, incidentally. You linked to the wrong part of the wiki.

Also, since the example you linked refers to a virus, and the example just below it refers to yeast (both of which have substantially higher mutation rates than humans do), it doesn't do a whole lot for your argument, especially in light of this, two paragraphs down: "In summary, it is generally accepted that the majority of mutations are neutral or deleterious, with rare mutations being advantageous; however, the proportion of types of mutations varies between species. This indicates two important points: first, the proportion of effectively neutral mutations is likely to vary between species, resulting from dependence on effective population size; second, the average effect of deleterious mutations varies dramatically between species.[53] In addition, the DFE also differs between coding regions and non-coding regions, with the DFE of non-coding DNA containing more weakly selected mutations.[53]"

In short, even deleterious mutations can be expressed as neutral ones, such as those that have no noticeable effect on an organism's fitness, or ones that are simply not expressed (due to being recessive).

Quote from: William

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Because more DNA changes are harmful than are beneficial, negative selection plays an important role in maintaining the long-term stability of biological structures by removing deleterious mutations. Thus, negative selection is sometimes also called purifying selection or background selection.

One study on the comparison of genes between different species of Drosophila suggests that if a mutation does change a protein, this will probably be harmful, with an estimated 70 percent of amino acid polymorphisms having damaging effects, and the remainder being either neutral or weakly beneficial

Granted, but these refer to a specific kind of mutation - ones that change amino acids. Moreover, the point I raised before about different organisms having different proportions of deleterious-to-neutral-to-beneficial mutations and different mutation rates applies here as well, since this appears to refer to flies rather than larger multicellular organisms.

Quote from: William

And the reference for the wiki quote above says:

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Our analysis suggests that approximately 95% of all nonsynonymous mutations that could contribute to polymorphism or divergence are deleterious, and that the average proportion of deleterious amino acid polymorphisms in samples is approximately 70%.

So the findings in different species and study methodologies confirm what I’m saying about most mutations being harmful. Of course many factors impact these studies and not all results can be perfectly adjusted for them. Dominant lethals, by their lethal nature, just don’t present themselves for study. Recessive lethals get purged in bottlenecks or bouts of local inbreeding. Some deleterious mutations can “surf” to higher frequencies on local waves of fecundity. Some are held in relatively stable polymorphisms by competing pressures e.g. the famous sickle cell anaemia example you quoted.

The problem is, the studies you've referred to have been about a particular kind of virus, yeast, and flies. All of which are prone to high rates of mutation, never mind the caveat I keep mentioning that those rates can easily differ between organisms.

Besides, I brought up a rather serious point in an earlier post regarding human mutation. Specifically, a study that stated that there were approximately 175 mutations per diploid genome (in humans), and that a conservative estimate of the deleterious mutation rate was 3 (out of 175). To elaborate on that, I looked for other studies. One stated that...here, I'll just quote the abstract.

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It has been suggested that humans may suffer a high genomic deleterious mutation rate. Here we test this hypothesis by applying a variant of a molecular approach to estimate the deleterious mutation rate in hominids from the level of selective constraint in DNA sequences. Under conservative assumptions, we estimate that an average of 4.2 amino-acid-altering mutations per diploid per generation have occurred in the human lineage since humans separated from chimpanzees. Of these mutations, we estimate that at least 38% have been eliminated by natural selection, indicating that there have been more than 1.6 new deleterious mutations per diploid genome per generation. Thus, the deleterious mutation rate specific to protein-coding sequences alone is close to the upper limit tolerable by a species such as humans that has a low reproductive rate, indicating that the effects of deleterious mutations may have combined synergistically. Furthermore, the level of selective constraint in hominid protein-coding sequences is atypically low. A large number of slightly deleterious mutations may therefore have become fixed in hominid lineages.

It is also very important to note that organisms such as viruses, yeast, and flies, are often used for genetic studies because they have an extremely high reproductive rate, which means that a high mutation rate is survivable. Humans, on the other hand, have a tiny fraction of this rate. So you simply cannot compare the mutation rate in humans (and other long-lived animals with low reproductive rates) to that of organisms that have extremely high reproductive rates. What that means is that the rate of deleterious mutations you cited in those other studies would not be survivable by humans - as noted in the two studies I linked, the rate of new deleterious mutations in human beings is 1-3 per generation.

Quote from: William

But the key to understanding the problem of damage caused by point mutations is that many genes make proteins (or regulate them). Proteins are not genetic information – they are 3D products that need to operate in a 3D molecular environment in which they’ve already adapted over many generations through natural selection. So structural proteins are quite sensitive to amino acid substitutions that alter their 3D structure, and in enzymes the 3D structure is particularly critical to catalytic function. It’s easier to stuff up the optimised 3D fit of folded proteins than it is to have changes with no effect or enhancements. But negative selection works steadily to cleanse the problems.

Granted, but at the same time, these proteins are more flexible than you seem to think they are. It's the receptor site that matters with a protein, not so much the general shape of the protein. So a mutation that affects some part of the general structure is not as likely to screw up the protein as one that affects the receptor site.

Quote from: William

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Furthermore, mutating an amino acid to a residue with significantly different properties could affect the folding and/or activity of the protein. There is therefore usually strong selective pressure to remove such mutations quickly from a population.